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Maryline Herbet

Insights into the role of genetic alterations in adrenocortical tumorigenesis

Published on 21 November 2008

Thesis presented November 21, 2008

Although molecular genetic alterations of benign (adenoma; ACA) and malignant (carcinoma; ACC) sporadic adrenocortical tumors are well established, their involvement in each step of the tumoral process, from initiation to metastatic tumors, is still unclear. Moreover, whether adenoma represents a separate entity or is in fact part of a process of tumor progression leading to the emergence of an ACC is still an open question. Genetic alterations commonly found in carcinomas are mutation in the proto-oncogene N-Ras (12.5%), mutation in the tumor suppressor gene TP53 (25%), mutation in ß-catenin gene (30%) and overexpression of IGF-2 (90%). We reproduced these alterations by overexpressing the oncogene RasG12V, the dominant negative p53DD, the mutant ß-cateninS37A and IGF-2 wild type. We thought to define a minimal genetic combination triggering fully tumorigenic transformation of primary bovine adrenocortical cells (BAC) in an in vivo tissue reconstruction model where cells are transplanted beneath the kidney capsule of immunodeficiente​ mice. Once transplanted into animals, cells overexpressing IFG-2 or ß-cateninS37A induced the formation of a murine tumor. Then, we failed to determine a combination using these two genes. Nevertheless, we showed that the simultaneous expression of RasG12V and p53DD is sufficient to convert primary cells into a fully tumorigenic state and that these genes cooperate through a precise sequence: only cells expressing first RasG12V and then p53DD become tumorigenic. Into this process, RasG12V induces an hyperplasic phenotype which progress into a malignant tumor after introduction of p53DD.
All together, our data have shown that the overexpression of an oncogene and the alteration of a tumor suppressor gene is sufficient to trigger ACC development (RasG12V and p53DD) and that the adrenocortical tumorigenesis is possibly a multi-step process. The mouse model proposed by this study could be a useful tool to define markers of malignancy and to design new therapeutic options for CCS treatments.

Adrenocortical tumorigenesis, adrenocortical carcinoma, in vivo model, RasG12V, p53DD, multi-step process

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